Skip to main content

Advertisement

SpringerLink
Log in

The protective role of curcumin in human dental pulp stem cells stimulated by lipopolysaccharide via inhibiting NF-κB p65 phosphorylation to suppress NLRP3 inflammasome activation

  • Research
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

This study aims to investigate the anti-inflammatory effect of curcumin and underlying mechanisms regarding the modulation of the nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome in human dental pulp stem cells (hDPSCs).

Materials and methods

The impact of curcumin on the viability of hDPSCs was evaluated. The effect of curcumin on the expression of IL-1β and NLRP3 in hDPSCs stimulated by lipopolysaccharide (LPS) was assessed. Then, LPS-primed hDPSCs were pre-treated with curcumin before ATP triggering NLRP3 inflammasome activation, and NLRP3 inflammasome-related mediators were assessed. The mechanism of curcumin inactivation of LPS plus ATP-induced inflammasome associated with NF-κB pathway was explored. The NF-κB pathway related pro-inflammatory mediators at mRNA and protein levels were evaluated. The expression of NF-κB p65 and phosphorylation p65 was visualized after curcumin or NF-κB inhibitor administrating respectively in hDPSCs with an activated NLRP3 inflammasome. Statistical analysis was performed.

Results

While curcumin at the concentration of 0.5–5 μM showed no obvious impact on the viability of hDPSCs, it significantly decreased IL-1β and NLRP3 mRNA expression in LPS-induced hDPSCs in a dose-dependent manner. Curcumin significantly inhibited the LPS plus ATP-primed NLRP3 inflammasome activation in hDPSCs (NLRP3, ASC, caspase-1, and IL-1β). Curcumin evidently attenuated the LPS plus ATP-induced expression of NF-κB pathway-related pro-inflammatory mediators (IL-6, IL-8, TNF-α, and COX-2). Furthermore, curcumin effectively reduced p65 phosphorylation, which acts as an NF-κB inhibitor in hDPSCs with an activated NLRP3 inflammasome.

Conclusions

Curcumin pre-treatment may exert an anti-inflammatory role via inactivation of the NLRP3 inflammasome by inhibiting NF-κB p65 phosphorylation in cultured hDPSCs.

Clinical relevance

Curcumin may have therapeutic potential in pulp inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zanini M, Meyer E, Simon S (2017) Pulp inflammation diagnosis from clinical to inflammatory mediators: a systematic review. J Endod 43:1033–1051. https://doi.org/10.1016/j.joen.2017.02.009

    Article  PubMed  Google Scholar 

  2. Schmidlin K, Schnell N, Steiner S, Salvi GE, Pjetursson B, Matuliene G, Zwahlen M, Bragger U, Lang NP (2010) Complication and failure rates in patients treated for chronic periodontitis and restored with single crowns on teeth and/or implants. Clin Oral Implants Res 21:550–557. https://doi.org/10.1111/j.1600-0501.2009.01907.x

    Article  PubMed  Google Scholar 

  3. Bjorndal L, Reit C, Bruun G, Markvart M, Kjaeldgaard M, Nasman P, Thordrup M, Dige I, Nyvad B, Fransson H, Lager A, Ericson D, Petersson K, Olsson J, Santimano EM, Wennstrom A, Winkel P, Gluud C (2010) Treatment of deep caries lesions in adults: randomized clinical trials comparing stepwise vs. direct complete excavation, and direct pulp capping vs. partial pulpotomy. Eur J Oral Sci 118:290–297. https://doi.org/10.1111/j.1600-0722.2010.00731.x

    Article  PubMed  Google Scholar 

  4. Marques MS, Wesselink PR, Shemesh H (2015) Outcome of direct pulp capping with mineral trioxide aggregate: a prospective study. J Endod 41:1026–1031. https://doi.org/10.1016/j.joen.2015.02.024

    Article  PubMed  Google Scholar 

  5. Muincharern W, Louwakul P, Pavasant P, Lertchirakarn V (2011) Effect of fluocinolone acetonide on human dental pulp cells: cytotoxicity, proliferation, and extracellular matrix formation. J Endod 37:181–184. https://doi.org/10.1016/j.joen.2010.10.013

    Article  PubMed  Google Scholar 

  6. Arora S, Cooper PR, Friedlander LT, Rizwan S, Seo B, Rich AM, Hussaini HM (2021) Potential application of immunotherapy for modulation of pulp inflammation: opportunities for vital pulp treatment. Int Endod J 54:1263–1274. https://doi.org/10.1111/iej.13524

    Article  PubMed  Google Scholar 

  7. Aggarwal BB, Sundaram C, Malani N, Ichikawa H (2007) Curcumin: the Indian solid gold. Adv Exp Med Biol 595:1–75. https://doi.org/10.1007/978-0-387-46401-5_1

    Article  PubMed  Google Scholar 

  8. Kahkhaie KR, Mirhosseini A, Aliabadi A, Mohammadi A, Mousavi MJ, Haftcheshmeh SM, Sathyapalan T, Sahebkar A (2019) Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmacology 27:885–900. https://doi.org/10.1007/s10787-019-00607-3

    Article  PubMed  Google Scholar 

  9. Fadus MC, Lau C, Bikhchandani J, Lynch HT (2017) Curcumin: an age-old anti-inflammatory and anti-neoplastic agent. J Tradit Complement Med 7:339–346. https://doi.org/10.1016/j.jtcme.2016.08.002

    Article  PubMed  Google Scholar 

  10. Nasra MM, Khiri HM, Hazzah HA, Abdallah OY (2017) Formulation, in-vitro characterization and clinical evaluation of curcumin in-situ gel for treatment of periodontitis. Drug Deliv 24:133–142. https://doi.org/10.1080/10717544.2016.1233591

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bhatia M, Urolagin SS, Pentyala KB, Urolagin SB, BM K, Bhoi S (2014) Novel therapeutic approach for the treatment of periodontitis by curcumin. J Clin Diagn Res 8:ZC65. https://doi.org/10.7860/JCDR/2014/8231.5343

    Article  PubMed  PubMed Central  Google Scholar 

  12. Guru SR, Kothiwale SV, Saroch N, Guru RC (2017) Comparative evaluation of inhibitory effect of curcumin and doxycycline on matrix metalloproteinase-9 activity in chronic periodontitis. Indian J Dent Res 28:560–565. https://doi.org/10.4103/ijdr.IJDR_461_16

    Article  PubMed  Google Scholar 

  13. Guimaraes MR, Coimbra LS, de Aquino SG, Spolidorio LC, Kirkwood KL, Rossa C Jr (2011) Potent anti-inflammatory effects of systemically administered curcumin modulate periodontal disease in vivo. J Periodontal Res 46:269–279. https://doi.org/10.1111/j.1600-0765.2010.01342.x

    Article  PubMed  PubMed Central  Google Scholar 

  14. Saharkhiz M, Ayadilord M, Emadian Razavi F, Naseri M (2022) Effects of phytosomal curcumin treatment on modulation of immunomodulatory and pulp regeneration genes in dental pulp mesenchymal stem cells. Odontology 110:287–295. https://doi.org/10.1007/s10266-021-00659-4

    Article  PubMed  Google Scholar 

  15. Ayadilord M, Nasseri S, Emadian Razavi F, Saharkhiz M, Rostami Z, Naseri M (2021) Immunomodulatory effects of phytosomal curcumin on related-micro RNAs, CD200 expression and inflammatory pathways in dental pulp stem cells. Cell Biochem Funct 39:886–895. https://doi.org/10.1002/cbf.3659

    Article  PubMed  Google Scholar 

  16. Sinjari B, Pizzicannella J, D'Aurora M, Zappacosta R, Gatta V, Fontana A, Trubiani O, Diomede F (2019) Curcumin/liposome nanotechnology as delivery platform for anti-inflammatory activities via NFkB/ERK/pERK pathway in human dental pulp treated with 2-hydroxyEthyl methacrylate (HEMA). Front Physiol 10:633. https://doi.org/10.3389/fphys.2019.00633

    Article  PubMed  PubMed Central  Google Scholar 

  17. Samiei M, Abedi A, Sharifi S, Maleki Dizaj S (2021) Early osteogenic differentiation stimulation of dental pulp stem cells by calcitriol and curcumin. Stem Cells Int 2021:9980137. https://doi.org/10.1155/2021/9980137

    Article  PubMed  PubMed Central  Google Scholar 

  18. Alipour M, Fadakar S, Aghazadeh M, Salehi R, Samadi Kafil H, Roshangar L, Mousavi E, Aghazadeh Z (2021) Synthesis, characterization, and evaluation of curcumin-loaded endodontic reparative material. J Biochem Mol Toxicol 35:e22854. https://doi.org/10.1002/jbt.22854

    Article  PubMed  Google Scholar 

  19. Horiba N, Maekawa Y, Matsumoto T, Nakamura H (1990) A study of the distribution of endotoxin in the dentinal wall of infected root canals. J Endod 16:331–334. https://doi.org/10.1016/S0099-2399(06)81944-8

    Article  PubMed  Google Scholar 

  20. Barthel CR, Levin LG, Reisner HM, Trope M (1997) TNF-alpha release in monocytes after exposure to calcium hydroxide treated Escherichia coli LPS. Int Endod J 30:155–159. https://doi.org/10.1046/j.1365-2591.1997.00066.x

    Article  PubMed  Google Scholar 

  21. Jung JY, Woo SM, Kim WJ, Lee BN, Nor JE, Min KS, Choi CH, Koh JT, Lee KJ, Hwang YC (2017) Simvastatin inhibits the expression of inflammatory cytokines and cell adhesion molecules induced by LPS in human dental pulp cells. Int Endod J 50:377–386. https://doi.org/10.1111/iej.12635

    Article  PubMed  Google Scholar 

  22. Lan C, Chen S, Jiang S, Lei H, Cai Z, Huang X (2022) Different expression patterns of inflammatory cytokines induced by lipopolysaccharides from Escherichia coli or Porphyromonas gingivalis in human dental pulp stem cells. BMC Oral Health 22:121. https://doi.org/10.1186/s12903-022-02161-x

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chen W, Guan Y, Xu F, Jiang B (2021) 4-Methylumbelliferone promotes the migration and odontogenetic differentiation of human dental pulp stem cells exposed to lipopolysaccharide in vitro. Cell Biol Int 45:1415–1422. https://doi.org/10.1002/cbin.11579

    Article  PubMed  Google Scholar 

  24. He W, Wang Z, Zhou Z, Zhang Y, Zhu Q, Wei K, Lin Y, Cooper PR, Smith AJ, Yu Q (2014) Lipopolysaccharide enhances Wnt5a expression through toll-like receptor 4, myeloid differentiating factor 88, phosphatidylinositol 3-OH kinase/AKT and nuclear factor kappa B pathways in human dental pulp stem cells. J Endod 40:69–75. https://doi.org/10.1016/j.joen.2013.09.011

    Article  PubMed  Google Scholar 

  25. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832. https://doi.org/10.1016/j.cell.2010.01.040

    Article  PubMed  Google Scholar 

  26. Chen M, Wang H, Chen W, Meng G (2011) Regulation of adaptive immunity by the NLRP3 inflammasome. Int Immunopharmacol 11:549–554. https://doi.org/10.1016/j.intimp.2010.11.025

    Article  PubMed  Google Scholar 

  27. Song Z, Lin Z, He F, Jiang L, Qin W, Tian Y, Wang R, Huang S (2012) NLRP3 is expressed in human dental pulp cells and tissues. Journal of Endodontics 38:1592–1597. https://doi.org/10.1016/j.joen.2012.09.023

    Article  PubMed  Google Scholar 

  28. Jiang W, Lv H, Wang H, Wang D, Sun S, Jia Q, Wang P, Song B, Ni L (2015) Activation of the NLRP3/caspase-1 inflammasome in human dental pulp tissue and human dental pulp fibroblasts. Cell Tissue Res 361:541–555. https://doi.org/10.1007/s00441-015-2118-7

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gong Z, Zhou J, Li H, Gao Y, Xu C, Zhao S, Chen Y, Cai W, Wu J (2015) Curcumin suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock. Mol Nutr Food Res 59:2132–2142. https://doi.org/10.1002/mnfr.201500316

    Article  PubMed  Google Scholar 

  30. Yin H, Guo Q, Li X, Tang T, Li C, Wang H, Sun Y, Feng Q, Ma C, Gao C, Yi F, Peng J (2018) Curcumin suppresses IL-1beta secretion and prevents inflammation through inhibition of the NLRP3 inflammasome. J Immunol 200:2835–2846. https://doi.org/10.4049/jimmunol.1701495

    Article  PubMed  Google Scholar 

  31. Al Madhoun A, Sindhu S, Haddad D, Atari M, Ahmad R, Al-Mulla F (2021) Dental pulp stem cells derived from adult human third molar tooth: a brief review. Front Cell Dev Biol 9:717624. https://doi.org/10.3389/fcell.2021.717624

    Article  PubMed  PubMed Central  Google Scholar 

  32. Chen J, Xu H, Xia K, Cheng S, Zhang Q (2021) Resolvin E1 accelerates pulp repair by regulating inflammation and stimulating dentin regeneration in dental pulp stem cells. Stem Cell Res Ther 12:75. https://doi.org/10.1186/s13287-021-02141-y

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chang J, Zhang C, Tani-Ishii N (2005) Shi S and Wang CJJodr. NF-kappaB activation in human dental pulp stem cells by TNF and LPS. 84:994–998. https://doi.org/10.1177/154405910508401105

    Article  Google Scholar 

  34. Zhang A, Wang P, Ma X, Yin X, Li J, Wang H, Jiang W, Jia Q, Ni L (2015) Mechanisms that lead to the regulation of NLRP3 inflammasome expression and activation in human dental pulp fibroblasts. Mol Immunol 66:253–262. https://doi.org/10.1016/j.molimm.2015.03.009

    Article  PubMed  Google Scholar 

  35. He Y, Hara H, Nunez G (2016) Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci 41:1012–1021. https://doi.org/10.1016/j.tibs.2016.09.002

    Article  PubMed  PubMed Central  Google Scholar 

  36. Bae WJ, Yi JK, Park J, Kang SK, Jang JH, Kim EC (2018) Lysyl oxidase-mediated VEGF-induced differentiation and angiogenesis in human dental pulp cells. Int Endod J 51:335–346. https://doi.org/10.1111/iej.12796

    Article  PubMed  Google Scholar 

  37. Attari F, Zahmatkesh M, Aligholi H, Mehr SE, Sharifzadeh M, Gorji A, Mokhtari T, Khaksarian M, Hassanzadeh G (2015) Curcumin as a double-edged sword for stem cells: dose, time and cell type-specific responses to curcumin. Daru 23:33. https://doi.org/10.1186/s40199-015-0115-8

    Article  PubMed  PubMed Central  Google Scholar 

  38. Arruda-Vasconcelos R, Louzada LM, Feres M, Tomson PL, Cooper PR, Gomes B (2021) Investigation of microbial profile, levels of endotoxin and lipoteichoic acid in teeth with symptomatic irreversible pulpitis: a clinical study. Int Endod J 54:46–60. https://doi.org/10.1111/iej.13402

    Article  PubMed  Google Scholar 

  39. Franchi L, Munoz-Planillo R, Nunez G (2012) Sensing and reacting to microbes through the inflammasomes. Nat Immunol 13:325–332. https://doi.org/10.1038/ni.2231

    Article  PubMed  PubMed Central  Google Scholar 

  40. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N, Mielke LA, Harris J, Coll RC, Mills KH, Mok KH, Newsholme P, Nunez G, Yodoi J et al (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11:897–904. https://doi.org/10.1038/ni.1935

    Article  PubMed  PubMed Central  Google Scholar 

  41. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361. https://doi.org/10.1038/nature08938

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232. https://doi.org/10.1038/nature04515

    Article  PubMed  Google Scholar 

  43. Gong Z, Zhao S, Zhou J, Yan J, Wang L, Du X, Li H, Chen Y, Cai W, Wu J (2018) Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1beta production. Mol Immunol 104:11–19. https://doi.org/10.1016/j.molimm.2018.09.004

    Article  PubMed  Google Scholar 

  44. Larochelle A, Bellavance M-A, Rivest S (2015) Role of adaptor protein MyD88 in TLR-mediated preconditioning and neuroprotection after acute excitotoxicity. Brain, Behavior, and Immunity 46:221–231. https://doi.org/10.1016/j.bbi.2015.02.019

    Article  PubMed  Google Scholar 

  45. Shen S, Shang L, Liu H, Liang Q, Liang W, Ge S (2021) AGGF1 inhibits the expression of inflammatory mediators and promotes angiogenesis in dental pulp cells. Clin Oral Investig 25:581–592. https://doi.org/10.1007/s00784-020-03498-9

    Article  PubMed  Google Scholar 

  46. Liu Z, Jiang T, Wang X, Wang Y (2013) Fluocinolone acetonide partially restores the mineralization of LPS-stimulated dental pulp cells through inhibition of NF-kappaB pathway and activation of AP-1 pathway. Br J Pharmacol 170:1262–1271. https://doi.org/10.1111/bph.12404

    Article  PubMed  PubMed Central  Google Scholar 

  47. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183:787–791. https://doi.org/10.4049/jimmunol.0901363

    Article  PubMed  Google Scholar 

  48. Mohanty C, Das M, Sahoo SK (2012) Sustained wound healing activity of curcumin loaded oleic acid based polymeric bandage in a rat model. Mol Pharm 9:2801–2811. https://doi.org/10.1021/mp300075u

    Article  PubMed  Google Scholar 

Download references

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

This research was funded by the Health Education Joint Project of Fujian Province (2019-WJ-14), and the Minjiang Scholar Fund of School and Hospital of Stomatology, Fujian Medical University (2018-KQMJ-01).

Author information

Authors and Affiliations

  1. Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatological Key Lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China

    Chunhua Lan, Yueming Qian, Yumin Wang, Yuemin Chen & Xiaojing Huang

  2. Institute of Stomatology & Research Center of Dental and Craniofacial Implants, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China

    Chunhua Lan, Yueming Qian, Yumin Wang, Yuemin Chen & Xiaojing Huang

  3. Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University, Fuzhou, China

    Chensheng Lin & Yanding Zhang

Authors
  1. Chunhua Lan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yueming Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yumin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuemin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chensheng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanding Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaojing Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chunhua Lan: investigation, data processing, and manuscript writing. Yueming Qian: methodology, project administration. Yumin Wang: reviewed and edited the manuscript. Yuemin Chen: investigation, resources. Chensheng Lin: investigation and resources. Yanding Zhang: technical support. Xiaojing Huang: conceptualization, funding acquisition, and reviewed and edited the manuscript.

Corresponding author

Correspondence to Xiaojing Huang.

Ethics declarations

Ethics approval

The use of human dental tissues was approved by the Ethics Committee of Fujian Medical University (approval No. 201652), and informed written consents were obtained from all participants.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lan, C., Qian, Y., Wang, Y. et al. The protective role of curcumin in human dental pulp stem cells stimulated by lipopolysaccharide via inhibiting NF-κB p65 phosphorylation to suppress NLRP3 inflammasome activation. Clin Oral Invest 27, 2875–2885 (2023). https://doi.org/10.1007/s00784-023-04885-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-023-04885-8

Keywords

Search

Navigation